Adenosine is a purine nucleoside which is known to act extracellularly to regulate different physiological processes through its binding to specific cell surface receptors (A1 and A2 receptors)(1,2,3). The fact that adenosine exerts an extracellular effect was demonstrated, for example, by an increased effect of adenosine on cells when given together with dipyridamole, which inhibits uptake of adenosine by cells(4).
Adenosine has been known to affect the cardiac rhythm and accordingly has been clinically used to protect the myocardium in various pathological situations(5,6). In addition, adenosine is also known as having both vasoconstrictor effect on the kidney and a vasodilator effect in other vascular beds. Adenosine is also known to have an effect on blood cells including: inhibition of platelet aggregation(7); stimulation of red blood cell hematopoiesis through the production of erythropoietin; exerting an anti-inflammatory effect manifested by inhibition of inflammatory cytokines(9,10); and reduction of septic shock. Adenosine was also shown to have a radioprotective effect when administered for a few minutes (about 15 mins) prior to the radiotherapeutic treatment(11).
Adenosine was also known to exert an anti-proliferative effect on cancer cells. Bajaj et al., 1983(12) noted that adenosine and adenosine analogs have a toxic effect on lymphocytic leukemia cells, which was more pronounced than the toxic effect on normal lymphocytes. Furthermore, Tey et al., 1992(13) showed that adenosine had an effect in modulating cell growth in human epidermoid carcinoma cells. In addition, it has been noted in the literature(14) that parenterally administered adenine nucleotides (AMP, ADP and ATP) inhibit tumor development in mice(15). ATP has been reported to increase Permeabilization of transformed cells(16,17), but it should be noted that ATP exerts its effect through the cellular receptors, P2X, P2Y and P2Z(18), which are different than that the A1 and A2 receptors through which adenosine exerts its regulatory effect.
White blood cells (leukocytes) consist of three basic groups of cells: granulocytes, monocytes and lymphocytes. Many therapeutic drug treatments have undesired side effects manifested in reduction of leukocytes, and particularly reduction in the count and relative proportion of granulocytes (which are typically 70% of the white blood cells), and particularly of neutrophils, which typically constitute more than about 90% out of the granulocytes. Examples of drugs which cause reduction in count of leukocytes, and particularly neutrophils, are cytotoxic drugs, e.g. such used in cancer chemotherapy, neuroleptic drugs, and others. The effect of reduction in white blood cell count is usually referred to in the art as “leukopenia” and reduction in the count of neutrophils as “neutropenia”. One major adverse effect of leukopenia, and particularly of neutropenia, is an increase in susceptibility of individuals to opportunistic infectious diseases. In many cases, particularly in cancer chemotherapy, the patients very often die from such opportunistic infectious diseases (e.g. from lung infection) and not from their primary disease, i.e. cancer. Drugs which can protect or inhibit the undesired toxic side effect of leukopenia, and particularly of neutropenia, would thus be highly desirable. Jackson et. al.(19) reviewed by Gentile et al.(20), showed that the toxic effect of two purine analogs (6-thioguanine and 6-mercaptopurine) on lymphoblaste and fibroblasts can be inhibited by adenosine. It was postulated that this effect is in view of the adenoine's inhibition of production of phosphoribosylpyrophosphate (PRPP). Jackson et al. point in the conclusion of their study to the possibility of developing cytotoxic drugs with a higher selectivity towards cancer cells, based on different enzyme patterns between tumor and normal cells. It should be noted that the work of Jackson et al. was conducted in vitro only, and when adenosine was tried in vivo, it was shown by Epstein et al.(21) that in vivo protection towards toxic effect of purine analog can be achieved with adenosine levels of about 500 mg/kg body weight. It should, however, be noted that at such mega doses, adenosine would likely be toxic and have a variety of side effects by itself.